Palbociclib Plus Fulvestrant Combo Maintains Long-Term OS Benefit


Palbociclib plus fulvestrant maintained a clinically meaningful overall survival improvement compared to placebo plus fulvestrant after a median follow-up of 73.3 months in patients with HR-positive, HER2-negative advanced breast cancer.

Palbociclib (Ibrance) plus fulvestrant (Faslodex) maintained a clinically meaningful overall survival (OS) improvement compared to placebo plus fulvestrant after a median follow-up of 73.3 months in patients with HR-positive, HER2-negative advanced breast cancer.1

Principal investigator Massimo Cristofanilli, MD, associate director for Translational Research at the Lurie Cancer Center and a professor of medicine in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, presented the findings during the 2021 ASCO Annual Meeting.

“An improvement in OS with palbociclib plus fulvestrant continues to be observed with more than 6 years of median follow up in patients with HR-positive advanced breast cancer who progressed on prior endocrine therapy,” Cristofanilli said. “This prolonged OS benefit is particularly evident in patients with endocrine-sensitive disease and those with prior exposure to chemotherapy in the advanced setting.”

The updated median OS in the experimental arm was 34.8 months versus 28.0 months in the placebo arm (stratified HR, 0.81; 95% CI, 0.65-0.99; 1-sided P = .0221). In findings reported after a median follow up of 44.8 months, the median OS was 34.9 months for palbociclib/fulvestrant compared with 28.0 months for placebo/fulvestrant (stratified HR, 0.81; 95% CI, 0.64-1.03; 1-sided P = .0429).

“Remarkable in this metastatic setting is that the 5-year OS rate is 23.3% in the palbociclib arm compared with 16.8% in the placebo arm,” he added.

Cristofanilli noted that 34% of patients had received prior chemotherapy for advanced breast cancer and 35% received more than 2 lines of prior treatment. He said that these types of patients had been excluded from other phase 3 studies testing CDK4/6 inhibitors with fulvestrant.

In patients who had not received prior chemotherapy for advanced disease, the median OS was 39.3 months in the experimental arm versus 29.7 months in the placebo arm (HR, 0.72; 95% CI, 0.55-0.94; P= .008). In contrast, there was no survival benefit for the combination in patients who did receive chemotherapy previously (24.6 vs 24.3 months; HR, 0.97; 95% CI, 0.69-1.36; P = .432).

Among those who were sensitive to prior hormonal therapy, 202 (73.7%) patients in the combination arm and 104 (76.5%) in the placebo group compared with 76.7% and 81.6%, respectively, among those who were not sensitive to hormone therapy. Cristofanilli said the largest group of patients were sensitive to endocrine therapy.

Investigators in the double-blind, phase 3 PALOMA-3 trial (NCT01942135) randomly assigned 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment to fulvestrant plus palbociclib (n = 347) or fulvestrant plus placebo (n = 174). The median age was 57 and 56 years in the palbociclib and placebo arms, respectively. Patients were stratified by menopausal status, sensitivity to prior hormonal therapy, and visceral metastases.

Palbociclib conferred an OS benefit regardless of ESR1 or PIK3CA mutation status, Cristofanilli said. Mutation status was prognostic for OS and highly associated with shorter OS in patients with ESR1 mutation. PIK3CA mutations were also associated with shorter OS, but the connection was weak.

The FDA approved palbociclib plus fulvestrant in February 2016 for women with pretreated HR-positive/HER2-negative metastatic breast cancer. The median progression-free survival was 9.5 months with palbociclib/fulvestrant compared with 4.6 months for placebo/fulvestrant (HR, 0.46; 95% CI, 0.36-0.59; P <.0001).

In June 2018, drugmaker Pfizer announced that palbociclib/fulvestrant combination failed to improve OS versus fulvestrant/placebo in PALOMA-3 for patients with HR-positive, HER2-negative metastatic breast cancer who received prior endocrine therapy. However, data presented at the 2018 ESMO Congress in October and simultaneously reported in the New England Journal of Medicine showed that the combination conferred a statistically significant 10.0-month OS improvement patients who were sensitive to previous endocrine therapy.2,3

More recently, findings presented during the AACR Annual Meeting 2021 in April showed that adding SDX-7320, a novel inhibitor of methionine aminopeptidase 2 (MetAP2), to palbociclib inhibited MCF-7 tumor growth and reduced the expression of proteins associated with resistance to palbociclib in orthotopic MCF-7 xenografts. The combination produced a greater tumor growth inhibition (TGI) rate than either agent alone.4

TGI was 49% with 8 mg/kg SDX-7320 and 65% for 40 mg/kg of palbociclib. The combination of 8 mg/kg SDX-7320 and 20 mg/kg palbociclib induced a TGI rate of 70%. When investigators increased the palbociblib dose to 40 mg/kg, the combination induced a TGI rate of 80%.

Furthermore, the addition of SDX-7320 to palbociclib reversed suppression of neutrophils seen with either agent alone. Palboclibib is associated with severe neutropenia and investigators hope the combination reduces incidence of the adverse event.


1. Cristofanilli M, Rugo HS, Im S, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J Clin Oncol. 2021;39(suppl 15):1000. doi:10.1200/JCO.2021.39.15_suppl.1000

2. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439. doi:10.1016/S1470-2045(15)00613-0

3. Cristofanilli M, Slamon DJ, Ro J, et al. Overall survival with palbociclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): analyses from PALOMA-3. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA2_PR.

4. Turner NC, Slamon DJ, Ro, I, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer [published online October 20, 2018].N Engl J Med. doi: 10.1056/NEJMoa1810527. Cornelius P, Mayers B, Dufour P, et al. SDX-7320, a novel inhibitor of methionine aminopeptidase 2 (MetAP2), inhibits MCF-7 tumor growth in combination with palbociclib (Ibrance). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Poster 1068.

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